Gattex

TEDUGLUTIDE

Added

1 year ago on 22 December 2016

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Indication(s)

1 INDICATIONS AND USAGE GATTEX® (teduglutide [rDNA origin]) for injection is indicated for the treatment of adult patients with Short Bowel Syndrome (SBS) who are dependent on parenteral support [see Clinical Pharmacology (12.2)]. GATTEX® (teduglutide [rDNA origin]) for injection is a glucagon-like peptide-2 (GLP-2) analog indicated for the treatment of adult patients with Short Bowel Syndrome (SBS) who are dependent on parenteral support. (1)

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Advisory information

6 ADVERSE REACTIONS The most common adverse reactions (≥10%) across all studies with GATTEX are abdominal pain, injection site reactions, nausea, headaches, abdominal distension, upper respiratory tract infection. In addition, vomiting and fluid overload were reported in the SBS studies (1 and 3) at rates ≥10%. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Shire-NPS Pharmaceuticals, Inc. at 1-800-828-2088 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice. Across all clinical studies, 595 subjects were exposed to at least one dose of GATTEX (249 patient-years of exposure; mean duration of exposure was 22 weeks). Of the 595 subjects, 173 subjects were treated in Phase 3 SBS studies (134/173 [77%] at the dose of 0.05 mg/kg/day and 39/173 [23%] at the dose of 0.10 mg/kg/day). The most commonly reported (≥ 10%) adverse reactions in subjects treated with GATTEX across all clinical studies (N=595) were: abdominal pain (31.3%); injection site reactions (21.8%); nausea (18.8%); headaches (16.3%); abdominal distension (14.8%); upper respiratory tract infection (11.9%). The rates of adverse reactions in subjects with SBS participating in 2 randomized, placebo-controlled, 24-week, double-blind clinical studies (Study 1 and Study 3) are summarized in Table 1. Only those reactions with a rate of at least 5% in the GATTEX group, and greater than placebo group, are summarized in Table 1. The majority of these reactions were mild or moderate. Of subjects receiving GATTEX at the recommended dose of 0.05 mg/kg/day, 88.3% (n=68/77) experienced an adverse reaction, as compared to 83.1% (n=49/59) for placebo. Many of these adverse reactions have been reported in association with the underlying disease and/or parenteral nutrition. Table 1: Adverse reactions in ≥5% of GATTEX-treated SBS subjects and more frequent than placebo: Studies 1 and 3 Adverse Reaction Placebo (N=59) n (%) GATTEX 0.05mg/kg/day (N=77) n (%) Abdominal Pain 16 ( 27.1) 29 ( 37.7) Upper Respiratory Tract Infection 8 ( 13.6) 20 ( 26.0) Nausea 12 ( 20.3) 19 ( 24.7) Abdominal Distension 1 ( 1.7) 15 ( 19.5) Vomiting 6 ( 10.2) 9 ( 11.7) Fluid Overload 4 ( 6.8) 9 ( 11.7) Flatulence 4 ( 6.8) 7 ( 9.1) Hypersensitivity 3 ( 5.1) 6 ( 7.8) Appetite Disorders 2 ( 3.4) 5 ( 6.5) Sleep Disturbances 0 4 ( 5.2) Cough 0 4 ( 5.2) Skin Hemorrhage 1 ( 1.7) 4 ( 5.2) Subjects with Stoma Gastrointestinal Stoma Complication 3 (13.6)Percentage based on 53 subjects with a stoma (n=22 placebo; n=31 GATTEX 0.05 mg/kg/day) 13 (41.9) In placebo-controlled Studies 1 and 3, 12% of patients in each of the placebo and GATTEX study groups experienced an injection site reaction. Adverse Reactions of Special Interest Malignancy Three subjects were diagnosed with malignancy in the clinical studies, all of whom were male and had received GATTEX 0.05 mg/kg/day in Study 2. One subject had a history of abdominal radiation for Hodgkin's disease two decades prior to receiving GATTEX and prior liver lesion on CT scan, and was diagnosed with metastatic adenocarcinoma of unconfirmed origin after 11 months of exposure to GATTEX. Two subjects had extensive smoking histories, and were diagnosed with lung cancers (squamous and non-small cell) after 12 months and 3 months of GATTEX exposure, respectively. Colorectal Polyps In the clinical studies, 13 subjects were diagnosed with polyps of the G.I. tract after initiation of study treatment. In the SBS placebo-controlled studies, 1/59 (1.7%) of subjects on placebo and 1/109 (0.9%) of subjects on GATTEX 0.05 mg/kg/day were diagnosed with intestinal polyps (inflammatory stomal and hyperplastic sigmoidal after 3 and 5 months, respectively). The remaining 11 polyp cases occurred in the extension studies – 2 colorectal villous adenomas (onset at 6 and 7 months in GATTEX 0.10 and 0.05 mg/kg/day dose groups, respectively), 2 hyperplastic polyp (onset 6 months in GATTEX 0.10 mg/kg/day dose group and 24 months in GATTEX 0.05 mg/kg/day dose group), 3 colorectal tubular adenomas (onset between 24 and 29 months in GATTEX 0.05 mg/kg/day dose group), 1 serrated adenoma (onset at 24 months in GATTEX 0.05 mg/kg/day dose group), 1 colorectal polyp biopsy not done (onset at 24 months in GATTEX 0.05 mg/kg/day dose group), 1 rectal inflammatory polyp (onset at 10 months in the GATTEX 0.05 mg/kg/day dose group, and 1 small duodenal polyp (onset at 3 months in GATTEX 0.05 mg/kg/day dose group). Gastrointestinal Obstruction Overall, 12 subjects experienced one or more episodes of intestinal obstruction/stenosis: 6 in SBS placebo-controlled studies and 6 in the extension studies. The 6 subjects in the placebo-controlled trials were all on GATTEX: 3/77 (3.9%) on GATTEX 0.05 mg/kg/day and 3/32 (9.4%) on GATTEX 0.10 mg/kg/day. No cases of intestinal obstruction occurred in the placebo group. Onsets ranged from 1 day to 6 months. In the extension studies, 6 additional subjects (all on GATTEX 0.05 mg/kg/day) were diagnosed with intestinal obstruction/stenosis with onsets ranging from 6 days to 19 months. Two of the 6 subjects from the placebo-controlled trials experienced recurrence of obstruction in the extension studies. Of all 8 subjects with an episode of intestinal obstruction/stenosis in these extension studies, 2 subjects required endoscopic dilation and 1 required surgical intervention. Gallbladder, Biliary and Pancreatic Disease For gallbladder and biliary disease in the placebo-controlled studies, 3 subjects were diagnosed with cholecystitis, all of whom had a prior history of gallbladder disease and were in the GATTEX 0.05 mg/kg/day dose group. No cases were reported in the placebo group. One of these 3 cases had gallbladder perforation and underwent cholecystectomy the next day. The remaining 2 cases underwent elective cholecystectomy at a later date. In the extension studies, 4 subjects had an episode of acute cholecystitis; 3 subjects had new-onset cholelithiasis; and 1 subject experienced cholestasis secondary to an obstructed biliary stent. For pancreatic disease in the placebo-controlled studies, 1 subject (GATTEX 0.05 mg/kg/day dose group) had a pancreatic pseudocyst diagnosed after 4 months of GATTEX. In the extension studies, 1 subject was diagnosed with chronic pancreatitis; and 1 subject was diagnosed with acute pancreatitis. Fluid Overload In the placebo-controlled trials, fluid overload was reported in 4/59 (6.8%) of subjects on placebo and 9/77 (11.7%) subjects on GATTEX 0.05 mg/kg/day. Of the 9 cases in the GATTEX group, there were 2 cases of congestive heart failure (CHF), 1 of whom was reported as a serious adverse event and the other as non-serious. The serious case had onset at 6 months, and was possibly associated with previously undiagnosed hypothyroidism and/or cardiac dysfunction. Concomitant Oral Medication GATTEX can increase the absorption of concomitant oral medications such as benzodiazepines and psychotropic agents. In the placebo-controlled trials, an analysis of episodes of cognition and attention disturbances was performed for subjects on benzodiazepines. One of the subjects in the GATTEX 0.05 mg/kg/day group (on prazepam) experienced dramatic deterioration in mental status progressing to coma during her first week of GATTEX therapy. She was admitted to the ICU where her benzodiazepine level was >300 mcg/L. GATTEX and prazepam were discontinued, and coma resolved 5 days later. 6.2 Immunogenicity Consistent with the potentially immunogenic properties of medicinal products containing peptides, administration of GATTEX may trigger the development of antibodies. Based on data from two trials in adults with SBS (a 6-month randomized placebo-controlled trial, followed by a 24-month open-label trial), the incidence of anti-teduglutide antibody was 3% (2/60) at Month 3, 18% (13/74) at Month 6, 25% (18/71) at Month 12, 31% (10/32) at Month 24 and 48% (14/29) at Month 30 in subjects who received subcutaneous administration of 0.05 mg/kg GATTEX once daily. The anti-teduglutide antibodies were cross-reactive to native glucagon-like peptide (GLP-2) in 5 of the 6 subjects (83%) who had anti-teduglutide antibodies. Anti-teduglutide antibodies appear to have no impact on short-term (up to 2.5 years) efficacy and safety although the long-term impact is unknown. In the same two trials, a total of 36 subjects were tested for neutralizing antibodies: 9 of these subjects had no neutralizing antibodies, and the remaining 27 subjects had no detectable neutralizing antibodies, although the presence of teduglutide at low levels in these study samples could have resulted in false negatives (no neutralizing antibody detected although present). Immunogenicity assay results are highly dependent on the sensitivity and specificity of the assay and may be influenced by several factors such as: assay methodology, sample handling, timing of sample collection, concomitant medication, and underlying diseases. For these reasons, comparison of the incidence of antibodies to GATTEX with the incidence of antibodies to other products may be misleading. 6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of GATTEX. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to GATTEX exposure. Cardiac disorders: Cardiac Arrest, Cardiac Failure Nervous system disorders: Cerebral Hemorrhage

Usage information

2 DOSAGE AND ADMINISTRATION The recommended once daily dose of GATTEX is 0.05 mg/kg. (2.1) Administer by subcutaneous injection; alternate sites between 1 of the 4 quadrants of the abdomen, or into alternating thighs or alternating arms. (2.1) For subcutaneous injection only. (2.1) For single-use only. Use within 3 hours after reconstitution, discard any unused portion. (2.5) 50% dosage reduction recommended in patients with moderate to severe renal impairment. (2.3) (8.6) (12.3) 2.1 Dosing Information The recommended daily dose of GATTEX is 0.05 mg/kg body weight administered by subcutaneous injection once daily. Alternation of sites for subcutaneous injection is recommended, and can include the thighs, arms, and the quadrants of the abdomen. GATTEX should not be administered intravenously or intramuscularly. If a dose is missed, that dose should be taken as soon as possible on that day. Do not take 2 doses on the same day. 2.2 Monitoring to Assess Safety A colonoscopy (or alternate imaging) of the entire colon with removal of polyps should be done within 6 months prior to starting treatment with GATTEX. A follow-up colonoscopy (or alternate imaging) is recommended at the end of 1 year of GATTEX. If no polyp is found, subsequent colonoscopies should be done no less frequently than every 5 years. If a polyp is found, adherence to current polyp follow-up guidelines is recommended. Patients should undergo initial laboratory assessments (bilirubin, alkaline phosphatase, lipase and amylase) within 6 months prior to starting treatment with GATTEX. Subsequent laboratory assessments are recommended every 6 months. If clinically meaningful elevation is seen, further diagnostic workup is recommended as clinically indicated (i.e., imaging of the biliary tract, liver, or pancreas) [see Warnings and Precautions (5.1) and (5.5)]. 2.3 Dosage Modifications in Renal Impairment Reduce the dose by 50% in patients with moderate and severe renal impairment (creatinine clearance less than 50 mL/min), and end-stage renal disease [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. 2.4 Discontinuation of Treatment Discontinuation of treatment with GATTEX may result in fluid and electrolyte imbalance. Therefore, patients' fluid and electrolyte status should be carefully monitored. 2.5 Preparation for Administration Reconstitute each vial of GATTEX by slowly injecting the 0.5 mL of preservative-free Sterile Water for Injection provided in the prefilled syringe. Allow the vial containing GATTEX and water to stand for approximately 30 seconds and then gently roll the vial between your palms for about 15 seconds. Do not shake the vial. Allow the mixed contents to stand for about 2 minutes. Inspect the vial for any undissolved powder. If undissolved powder is observed, gently roll the vial again until all material is dissolved. Do not shake the vial. If the product remains undissolved after the second attempt, do not use. GATTEX does not contain any preservatives and is for single-use only. Discard any unused portion. The product should be used within 3 hours after reconstitution [see How Supplied/Storage and Handling (16.2)].

8 USE IN SPECIFIC POPULATIONS The safety and efficacy of GATTEX in pediatric patients have not been established. (8.4) 8.1 Pregnancy Category B Risk Summary Adequate and well-controlled studies with GATTEX have not been conducted in pregnant women. In animal reproduction studies, no effects on embryo-fetal development were observed with the administration of subcutaneous teduglutide at doses up to 1000 times the recommended human dose in both rats and rabbits. Because animal reproductive studies are not always predictive of human response, GATTEX should be used during pregnancy only if clearly needed. Data Animal data In animal studies, no effects on embryo-fetal development were observed in pregnant rats given subcutaneous teduglutide at doses up to 50 mg/kg/day (about 1000 times the recommended daily human dose of 0.05 mg/kg) or pregnant rabbits given subcutaneous doses up to 50 mg/kg/day (about 1000 times the recommended daily human dose of 0.05 mg/kg). A pre- and postnatal development study in rats showed no evidence of any adverse effect on pre- and postnatal development at subcutaneous doses up to 50 mg/kg/day (about 1000 times the recommended daily human dose of 0.05 mg/kg). 8.3 Nursing Mothers It is not known whether GATTEX is present in human milk. Teduglutide is excreted in the milk of lactating rats, and the highest concentration measured in milk was 2.9% of the plasma concentration following a single subcutaneous injection of 25 mg/kg. Because many drugs are excreted in human milk, because of the potential for serious adverse reactions to nursing infants from GATTEX and because of the potential for tumorigenicity shown for teduglutide in mice and rats, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use Safety and efficacy in pediatric patients have not been established. 8.5 Geriatric Use No dose adjustment is necessary in patients above the age of 65 years. Of the 595 subjects treated with teduglutide, 43 subjects were 65 years or older, whereas 6 subjects were 75 years of age or older. In the SBS studies, no overall differences in safety or efficacy were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3)]. 8.6 Renal Impairment Reduce the dose of GATTEX by 50% in patients with moderate and severe renal impairment (creatinine clearance less than 50 mL/min) and end-stage renal disease (ESRD) [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment GATTEX has not been formally studied in subjects with severe hepatic impairment. No dosage adjustment is necessary for patients with mild and moderate hepatic impairment based on a study conducted in Child-Pugh grade B subjects [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

8.3 Nursing Mothers It is not known whether GATTEX is present in human milk. Teduglutide is excreted in the milk of lactating rats, and the highest concentration measured in milk was 2.9% of the plasma concentration following a single subcutaneous injection of 25 mg/kg. Because many drugs are excreted in human milk, because of the potential for serious adverse reactions to nursing infants from GATTEX and because of the potential for tumorigenicity shown for teduglutide in mice and rats, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother [see Nonclinical Toxicology (13.1)].

Interactions

7 DRUG INTERACTIONS GATTEX has the potential to increase absorption of concomitant oral medications. Careful monitoring and possible dose adjustment of oral medications that require titration or have a narrow therapeutic index is recommended. (5.5) (7.1) 7.1 Potential for Increased Absorption of Oral Medications Based upon the pharmacodynamic effect of GATTEX, there is a potential for increased absorption of concomitant oral medications, which should be considered if these drugs require titration or have a narrow therapeutic index [see Warnings and Precautions (5.5)]. 7.2 Concomitant Drug Therapy Clinical interaction studies were not performed. No inhibition or induction of the cytochrome P450 enzyme system has been observed based on in vitro studies although the relevance of in vitro studies to an in vivo setting is unknown.

More information

Category

Value

Authorisation number

NDA203441

Agency product number

7M19191IKG

Orphan designation

No

Product NDC

68875-0101,68875-0102,68875-0103

Date Last Revised

18-10-2016

Type

HUMAN PRESCRIPTION DRUG

Storage and handling

16.2 Storage and Handling Prior to Dispensing: Store refrigerated at 2°C to 8°C (36°F to 46°F) for Cartons of Drug Vials and the One-vial kits. Do not freeze. Do not use beyond the expiration date on the label. Store at room temperature up to 25°C (77°F) for the Cartons of Ancillary Supplies. Instruction for the Pharmacist: Prior to Dispensing: Store at 2°C to 8°C (36°F to 46°F) for Cartons of Drug Vials and the One-vial kits. Do not freeze. Dispensing Instructions: Dispense with a 90-day "use by" dating and specify "Store at room temperature up to 25°C (77°F). Do not freeze." Dispense Medication Guide to each patient. Reconstituted GATTEX is a sterile, clear, colorless to light straw-colored solution, which should be free from particulates. The drug should be completely dissolved before the solution is withdrawn from the vial. Do not shake or freeze the reconstituted solution. If the product remains undissolved after the second attempt, do not use. GATTEX does not contain any preservatives and is for single-use only. Any unused portion should be discarded. The product should be used within 3 hrs after reconstitution.